Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants

ABSTRACT

Methods and pharmaceutical compositions employing (+) cetirizine, (−) cetirizine, or racemic cetirizine, or a pharmaceutically acceptable salt thereof, and a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, or decongestant for the treatment, management, and/or prevention of inflammation, asthma or symptoms thereof, allergic disorders such as allergic rhinitis, and dermatitis.

1. FIELD OF THE INVENTION

[0001] The invention relates to methods of prevention and treatmentusing, and pharmaceutical compositions containing, cetirizine and aleukotriene inhibitor.

2. BACKGROUND OF THE INVENTION

[0002] In its racemic form, cetirizine, chemically named2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid,is an orally active, potent, long acting peripheral histamine H₁receptor antagonist. See, e.g., Juhlin, L., et al. J. Allergy Clin.Immunol. 80:599-602 (1987); De Vos, C., et al. Annal. Allergy 59:278-282(1987); U.S. Pat. No. 4,525,358. Cetirizine is a second generation H₁histamine receptor antagonist that generally offers some significantadvantages beyond the first generation compounds. These advantagesinclude: (1) less sedation, (2) little anticholinergic activity, and (3)longer duration of activity. The medicinal chemistry of cetirizine isdescribed by Campoli-Richards et al., Drugs 40:762-781(1990), Snyder andSnowman, Allergy 59II:4-8(1987), and Rihoux and DuPont, Annals ofAllergy 59:235-238(1987).

[0003] Cetirizine has been employed in the treatment of some symptoms ofallergic reactions. For example, U.S. Pat. No. 5,419,898 to Ikejiri etal. discloses antiallergic compositions containing cetirizine forophthalmic or nasal use. Its efficacy in the treatment of some othersymptoms associated with asthma, however, is limited. Specifically,clinical studies conducted by Gong and coworkers revealed that thecompound, when administered to patients in doses as large as 20 mg, isnot uniformly effective in preventing allergen- or exercise-inducedbronchoconstriction (Gong, H., et al. J. Allergy Clin. Immunol.85:632-641 (1990)).

[0004] In only a few cases has cetirizine been combined with other drugsfor the treatment of disease. For example, U.S. Pat. No. 4,829,064 toSunshine et al. discloses compositions useful for treating cold symptomscomprising cetirizine and an analgesic. Published European PatentApplication No. 433766 A1 to York et al. discloses compositions ofcetirizine and an antiallergic compound useful for treating ophthalmicallergic responses.

[0005] Although the stereoselectivity of some drugs is well known (see,e.g., Ariens, E. J. Schweiz. Med. Wocheuschr. 120:131-134 (1994)),disclosures directed to the combination of cetirizine with other drugshave taught away from combinations comprising optically pure enantiomersof cetirizine. Recently, however, some advantages of treating certaindiseases with an optically pure enantiomer of cetirizine alone has beenrecognized.

[0006] U.S. Pat. No. 5,627,183 discloses methods of treating urticariausing optically pure (+) cetirizine. U.S. Pat. No. 5,698,558 disclosesmethods of treating certain allergic disorders using (−) cetirizine.Both patents disclose that the administration of optically pureenantiomers of cetirizine can reduce or avoid adverse side effectsassociated with the use of racemic cetirizine. These side effectsinclude sedation and somnolence, headache, gastrointestinal disturbance,dizziness, nausea, cardiac arrhythmias, and other cardiovasculareffects. Such adverse effects are common to non-sedating antihistamines.

[0007] It has been suggested that the moderate effectiveness of someH₁-antihistamines is due in part to their additional activity againstleukotrienes, particularly leukotriene D₄ (LTD₄). Leukotrienes augmentneutrophil and eosinophil migration, neutrophil and monocyteaggregation, leukocyte adhesion, increase capillary permeability, andsmooth muscle contraction, all of which contribute to inflammation,edema, mucus secretion, and bronchoconstriction.

[0008] In one study of guinea pigs, the increase in airway resistancecaused by LTD₄ was suppressed by the antihistamine terfenadine. SeeAkagi et al., Oyo Yakuri, 35: 361-371 (1988). In another study, twentyH₁-antihistamines with diverse chemical structures were tested foractivity against LTD₄-induced contraction in isolated guinea-pig ileumand displacement of [³H]LTD₄ from guinea-pig lung membrane proteins (M.Zhang et al., Inflamm. res. 46:Supp. I S93-S94 (1997)). The resultsindicated the drugs were weakly active in inhibiting LTD₄-inducedcontraction of guinea pig ileum.

[0009] A number of drugs have been designed specifically to inhibitleukotriene formation. One of these, zileuton, is a specific inhibitorof 5-lipoxygenase. Commercially available as ZYFLO®, it has the chemicalname (±)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is knownto inhibit leukotriene (LTH₄, LTC₄, LTD₄, and LTE₄) formation in vitro.Zileuton is an inhibitor ex vivo of LTB₄ formation in several speciesand inhibits leukotriene-dependent smooth muscle contractions in vitroin guinea pig and human airways. One study of 373 patients indicatedthat 600 mg of zileuton four times daily were required to provideefficacy, while 400 mg failed to do so. In some patients, zileuton wasreported to cause headache, pain, asthenia, dyspepsia, nausea, andmyalgia (Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 474-76 (1998)).

[0010] Zafirlukast, sold commercially as ACCOLATE®, is another type ofleukotriene inhibitor. This leukotriene inhibitor is a leukotrienereceptor antagonist (LTRA) of leukotriene D₄ and E₄, and has thechemical name4-(5-cyclopentyloxycarbonylamino-1-methyl-indol-8-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide.Cysteinyl leukotriene production and receptor occupation have beencorrelated with the pathophysiology of asthma. In vitro studiesindicated that zafirlukast antagonized the contractile activity of threeleukotrienes in conducting airway smooth muscle from laboratory animalsand humans; prevented intradermal LTD₄-induced increases in cutaneousvascular permeability; and inhibited inhaled LTD₄-induced influx ofeosinophils into animal lungs. In some patients, zafirlukast has beenreported to cause headache, infection, nausea, diarrhea, pain, asthenia,abdominal pain, dizziness, myalgia, fever, vomiting, SGPT elevation, anddyspepsia (Physician's Desk Reference, 52 ed., Medical Economics Co.,Inc., 3148-49 (1998)).

3. SUMMARY OF THE INVENTION

[0011] The present invention represents an improvement over both thecetirizine and the leukotriene inhibitor technology presently available.

[0012] This invention relates to novel pharmaceutical compositionscomprising: (a) an optically pure enantiomer of cetirizine, a racemicmixture of cetirizine, or a pharmaceutically acceptable salt thereof;and (b) a leukotriene inhibitor. These compositions may optionallycontain an additional ingredient, such as a decongestant.

[0013] The compositions of the present invention are believed to improveupon, and are superior to, those of the prior art used to treat orprevent asthma, asthma symptoms, inflammation, allergic disorders suchas allergic rhinitis, and dermatitis. Unexpectedly, it is believed thatthere is a synergistic effect when cetirizine, or an enantiomer or saltthereof, is used in combination with one or more leukotriene inhibitors.Both racemic and optically pure enantiomers of cetirizine may be used toachieve this synergistic effect. Furthermore, the compositions andmethods of this invention avoid or reduce certain adverse side effectsassociated with second generation H₁ histamine receptor antagonists.

[0014] The compositions of this invention possess potent antihistaminicactivity. They are useful for treating and preventing the occurrence ofasthma or asthma symptoms. They are also useful for the treatment andprevention of dermatitis, inflammation, and allergic disorders such asallergic rhinitis. The compositions of this invention may also be usedto threat the symptoms of allergic asthma, allergic rhinitis, and otherallergic disorders, as well as dermatitis. In addition, the compositionsof the invention reduce or avoid adverse effects generally associatedwith administration of non-sedating antihistamines, such as racemiccetirizine or an enantiomer of cetirizine. Adverse effects include, butare not limited to, cardiac arrhythmias, drowsiness, nausea, fatigue,weakness and headache.

[0015] The compositions of this invention are also useful in combinationwith non-steroidal anti-inflammatory agents or other non-narcoticanalgesics for the treatment or prevention of inflammation, cough, cold,cold-like, and/or flu symptoms and the discomfort, headache, pain,fever, and general malaise associated therewith. The aforementionedcombinations (e.g., an enantiomer or racemic mixture of cetirizine and aleukotriene inhibitor) may optionally include one or more other activecomponents including a decongestant, cough suppressant/antitussive, orexpectorant.

[0016] Additionally, the novel pharmaceutical compositions of theinvention are useful in treating, preventing, or managing motionsickness, vertigo, diabetic retinopathy, small vessel complications dueto diabetes and such other conditions as may be related to the activityof these derivatives as antagonists of the H₁ histamine receptor. Thecompositions can be used to treat or prevent these disorders whilereducing or avoiding adverse effects associated with administration ofnon-sedating antihistamines.

[0017] In one embodiment, this invention provides for a method oftreating or preventing asthma or asthma symptoms in a human whichcomprises administering to a human a therapeutically effective amount ofan optically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof. Preferably, the leukotriene inhibitor is a5-lipoxygenase inhibitor or a 5-lipoxygenase activating proteinantagonist.

[0018] The invention also provides a method of treating or preventingasthma or asthma symptoms in a human comprising administering to a humana composition, said composition comprising (i) a therapeuticallyeffective amount of an optically pure enantiomer of cetirizine, racemiccetirizine, or a pharmaceutically acceptable salt thereof; (ii) aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,selected from the group consisting of 5-lipoxygenase inhibitors,5-lipoxygenase activating protein antagonists, and leukotriene receptorantagonists; and a pharmaceutically acceptable carrier or excipient.

[0019] This invention is further directed to a method of treating orpreventing asthma or the symptoms of asthma in a human which comprisesadministering to a human therapeutically effective amounts of anoptically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, a leukotriene inhibitor, or apharmaceutically acceptable salt thereof, and a decongestant.Preferably, the leukotriene inhibitor is a 5-lipoxygenase inhibitor or a5-lipoxygenase activating protein antagonist.

[0020] In a second embodiment, the invention provides for a method oftreating or preventing dermatitis in a human which comprisesadministering to a human a therapeutically effective amount of anoptically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, and a leukotriene inhibitor,or a pharmaceutically acceptable salt thereof.

[0021] In a third embodiment, the invention provides for a method oftreating or preventing allergic rhinitis in a human which comprisesadministering to a human a therapeutically effective amount of anoptically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, and a leukotriene inhibitor,or a pharmaceutically acceptable salt thereof. Preferably, theleukotriene inhibitor is a 5-lipoxygenase inhibitor or a 5-lipoxygenaseactivating protein antagonist.

[0022] In a fourth embodiment, the invention provides for a method oftreating or preventing inflammation in a human which comprisesadministering to a human a therapeutically effective amount of anoptically pure enantiomer of cetirizine, racemic cetirizine, or apharmaceutically acceptable salt thereof, and a leukotriene inhibitor,or a pharmaceutically acceptable salt thereof.

[0023] In a fifth embodiment, the invention provides for a method ofpreventing or treating a condition responsive to leukotriene inhibitionwhich comprises administering to a human a therapeutically effectiveamount of cetirizine, or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,and optionally a decongestant, or a pharmaceutically acceptable saltthereof.

[0024] The invention encompasses the treatment, prevention, and/ormanagement of these disorders using a single unit dosage form thatcontains an optically pure enantiomer of cetirizine or racemiccetirizine, or a pharmaceutically acceptable salt thereof, and aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,such that the cetirizine component and leukotriene inhibitor are in onesolid or liquid dosage form. It should be recognized, however, thatcombination therapy by separate administration of each active ingredientis also contemplated. Consequently, the administration of the activeingredients (i.e., optically pure or racemic cetirizine and leukotrieneinhibitor, and optionally decongestant) of this invention may beconcurrent or sequential. For example, a cetirizine component and aleukotriene inhibitor may be administered as a combination, concurrentlybut separately, or by the sequential administration of cetirizine andleukotriene inhibitor or the sequential administration of a leukotrieneinhibitor and cetirizine. Cetirizine may be administered in a similarmanner with a decongestant.

4. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention encompasses the treatment, prevention,and/or management of asthma, the symptoms of asthma, dermatitis,inflammation, or allergic disorders, such as allergic rhinitis, using anoptically pure enantiomer of cetirizine or racemic cetirizine, or apharmaceutically acceptable salt thereof, in combination with aleukotriene inhibitor; and optionally a decongestant.

[0026] According to the present invention, all means of treatment,prevention, and/or management of these disorders, including, but notlimited to, topical, local, and systemic, may employ racemic cetirizine,optically pure (+) cetirizine or (−) cetirizine, or a pharmaceuticallyacceptable salt thereof. It is preferred, however, that (+) cetirizine,or a pharmaceutically acceptable salt thereof, in combination with aleukotriene inhibitor, and optionally a decongestant, be used for thetopical or local treatment, prevention, and/or management of dermatitis,inflammation, or related disorders. It is preferred that (−) cetirizine,or a pharmaceutically acceptable salt thereof, be used in combinationwith a leukotriene inhibitor, and optionally a decongestant, for thesystemic treatment of asthma, the symptoms of asthma, or allergicdisorders, such as allergic rhinitis.

[0027] Without being limited by theory, it is believed that (−)cetirizine generally has a lower affinity towards the cortex histaminereceptor than (+) cetirizine. Consequently, the administration of (−)cetirizine in combination with a leukotriene inhibitor and optionally adecongestant may have fewer undesirable effects on the central nervoussystem, such as sedation or drowsiness, than would result fromadministration of the corresponding (+) cetirizine combination. At thesame time, (+) cetirizine is able to inhibit the effects of histaminepresent in high local concentrations. For at least this reason, topicalor local treatment, prevention, and/or management of inflammation andother disorders may be more effective with the administration of (+)cetirizine in combination with a leukotriene inhibitor and optionally adecongestant than with the administration of the corresponding (−)cetirizine combination.

[0028] It should be recognized that the invention includes the use ofthe cetirizine active ingredient and the leukotriene inhibitor as acombination either in a single composition, or separately butconcurrently and/or sequentially. The same is true when an optionaldecongestant is used.

[0029] The methods and compositions of this invention are believed toreduce or avoid adverse effects associated with administration ofnon-sedating antihistamines, and particularly with administration ofracemic cetirizine alone. The methods and compositions described hereinare believed to provide superior or improved therapy over prior artmethods and compositions involving optically pure or racemic cetirizinein the absence of a leukotriene inhibitor, or a leukotriene inhibitor inthe absence of optically pure or racemic cetirizine. Without beinglimited by theory, it is believed that the combination of optically pureor racemic cetirizine, or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,and optionally a decongestant, provides superior, improved, andsynergistic effects unachievable by any of these compounds alone.

[0030] The preparation of racemic cetirizine can be performed by themethods described in U.S. Pat. No. 2,899,436 to Morren et al., U.S. Pat.No. 4,525,358 to Bates et al., or by an improved procedure described inBritish Application No. 2,225,320 of Cossement et al., the disclosuresof which are hereby expressly incorporated herein by reference theretofor this purpose. Synthesis of substantially optically pure (+) and (−)enantiomers of cetirizine is described in British Application No.2,225,320 of Cossement et al., as well as in U.S. Pat. No. 5,478,941 toCossement et al., the disclosures of which are also expresslyincorporated herein by reference thereto. Alternatively, the opticallypure enantiomers can be resolved from the racemic mixture using standardtechniques available in the art.

[0031] As used herein, the terms “adverse effects” and “adverse sideeffects” include, but are not limited to, cardiac arrhythmias, cardiacconduction disturbances, appetite stimulation, weight gain, sedation,gastrointestinal distress, headache, dry mouth, constipation, anddiarrhea. The term “cardiac arrhythmias” includes, but is not limitedto, ventricular tachyarrhythmias, torsades de pointes, and ventricularfibrillation.

[0032] The term “asthma” as used herein is defined as a disordercharacterized by increased responsiveness of the trachea and bronchi tovarious stimuli, which results in symptoms that include, but are notlimited to, wheezing, cough, shortness of breath, dyspnea, and the like.Asthma includes, for example, allergic asthma.

[0033] The term “dermatitis” as used herein is that disorder caused byinflammation to the skin including endogenous and contact dermatitissuch as, but not limited to: actinic dermatitis (or photodermatitis),atopic dermatitis, chemical dermatitis, cosmetic dermatitis, dermatitisaestivalis, and seborrheic dermatitis.

[0034] As used herein, the term “pharmaceutically acceptable salt”refers to a salt prepared from pharmaceutically acceptable non-toxicacids or bases including inorganic acids or bases or organic acids orbases. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, sulfuric, and phosphoric. Appropriate organic acids may beselected, for example, from aliphatic, aromatic, carboxylic and sulfonicclasses of organic acids, examples of which are formic, acetic,propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic,benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic,stearic, sulfanilic, algenic, and galacturonic. Examples of suchinorganic bases include metallic salts made from aluminum, calcium,lithium, magnesium, potassium, sodium, and zinc. Appropriate organicbases may be selected, for example, from N,N-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine(N-methylglucamine), lysine and procaine.

[0035] The terms “substantially optically pure,” “optically pure,” and“optically pure enantiomers” as used herein mean that the compositioncontains greater than about 95% of the desired enantiomer by weight,preferably greater than about 98% of the desired enantiomer by weight,and most preferably greater than about 99% of the desired enantiomer byweight, said percent based upon the total weight of cetirizine. In otherwords, the term “substantially free” means less than about 5 weightpercent, preferably less than about 2 weight percent, and morepreferably less than about 1 weight percent.

[0036] The term “cetirizine” when used without modification means thecompound in all its forms, including, but not limited to, racemiccetirizine, optically pure enantiomers of cetirizine, and mixturesthereof.

[0037] The term “racemic” as used herein means a mixture of the (+) and(−) enantiomers of a compound wherein the (+) and (−) enantiomers arepresent in approximately a 1:1 ratio.

[0038] The phrase “therapeutically effective amount of cetirizine” asused herein means that amount of optically pure or racemic cetirizine,or a pharmaceutically acceptable salt thereof, which, alone or incombination with other drugs, provides a therapeutic benefit in thetreatment, management, or prevention of conditions that are responsiveto histamine antagonists, such as asthma, asthma symptoms, allergicdisorders such as allergic rhinitis, and dermatitis.

[0039] The phrase “therapeutically effective amount of leukotrieneinhibitor” as used herein means that amount of leukotriene inhibitorwhich alone, or in combination with other drugs, provides a therapeuticbenefit in the treatment, management, or prevention of any conditionthat is responsive to leukotriene inhibitors, such as asthma, asthmasymptoms, inflammation, allergic disorders such as allergic rhinitis,and dermatitis.

[0040] The phrase “therapeutically effective amount of a decongestant”as used herein means that amount of decongestant which alone, or incombination with other drugs, provides a therapeutic benefit in thetreatment, management, or prevention of congestion of the respiratorytract and/or sinus.

[0041] The term “leukotriene inhibitor” as used herein includes anyagent or compound that inhibits, restrains, retards or otherwiseinteracts with the action or activity of leukotrienes, such as, but notlimited to, 5-lipoxygenase (“5-LO”) inhibitors, 5-lipoxygenaseactivating protein (“FLAP”) antagonists, and leukotriene receptorantagonists (“LTRAs”).

[0042] The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” as usedherein includes any agent or compound that inhibits, restrains, retardsor otherwise interacts with the enzymatic action of 5-lipoxygenase, suchas, but not limited to, zileuton, docebenone, piripost, and ICI-D2318.

[0043] The term “5-lipoxygenase activating protein antagonist” or “FLAPantagonist” as used herein includes any agent or compound that inhibits,restrains, retards or otherwise interacts with the action or activity of5-lipoxygenase activating protein, such as, but not limited to, MK-591and MK-886.

[0044] The term “leukotriene receptor antagonist” or “LTRA” as usedherein includes any agent or compound that inhibits, restrains, retardsor otherwise antagonizes the activity of receptors that are responsiveto leukotrienes, including those responsive to leukotriene D₄. ExemplaryLTRAs include sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)-ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)-cyclopropaneacetate,1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneaceticacid or salts thereof, pranlukast, zafirlukast (ICI-204219), andmontelukast (MK-476), the latter of which is sold commercially asSINGULAIR®.

[0045] The magnitude of a prophylactic or therapeutic dose of opticallypure or racemic cetirizine or leukotriene inhibitor in the acute orchronic prevention, treatment, or management of a disorder or conditionwill vary with the severity of the condition to be treated and the routeof administration. The dose, and perhaps the dose frequency, will alsovary according to the age, body weight, and response of the individualpatient. The magnitude of the dose may also depend upon whetheroptically pure or racemic cetirizine is used. Furthermore, if anoptically pure enantiomer of cetirizine is used, the magnitude of thedose may depend upon whether it is the (+) or (−) enantiomer. Suitabletotal daily dose ranges can be readily determined by those skilled inthe art. In general, the total daily dose range for optically pure orracemic cetirizine, for the conditions described herein, is from about0.01 mg to about 50 mg administered in single or divided doses. Forexample, a preferred oral daily dose range should be from about 1 mg toabout 30 mg. A more preferred oral dose is about 5 mg to about 25 mg. Apreferred oral daily dose range of decongestant, such aspseudoephedrine, should be from about 50 mg to about 300 mg, morepreferably, about 150 mg to about 250 mg. In addition, suitable oraldaily dosage ranges of leukotriene inhibitor can be readily determinedby those skilled in the art (see, e.g., Physician's Desk Reference). Forexample, for 5-lipoxygenase inhibitors, a preferred oral daily doserange of leukotriene inhibitor should typically be from about 20 mg to2,500 mg, preferably about 20 mg to 800 mg. For leukotriene receptorantagonists, a preferred oral daily dose of leukotriene inhibitor shouldtypically be from about 2 mg to 100 mg, preferably about 5 mg to 20 mg.

[0046] It is further recommended that children, patients aged over 65years, and those with impaired renal or hepatic function initiallyreceive low doses, and that they then be titrated based on individualresponse(s) or blood level(s). It may be necessary to use dosagesoutside these ranges in some cases as will be apparent to those skilledin the art. Further, it is noted that the clinician or treatingphysician will know how and when to adjust, interrupt, or terminatetherapy in conjunction with individual patient response.

[0047] Any suitable route of administration may be employed forproviding the patient with an effective dosage of an optically pure orracemic cetirizine and leukotriene inhibitor according to the methods ofthe present invention. For example, oral, intraoral, rectal, parenteral,epicutaneous, transdermal, subcutaneous, intramuscular, intranasal,sublingual, buccal, intradural, intraocular, intrarespiratory, or nasalinhalation and like forms of administration may be employed. Oraladministration is generally preferred. For the methods to treatdermatitis, however, topical administration is preferred.

[0048] The pharmaceutical compositions used in the methods of thepresent invention, which are sterile and stable, include optically pureor racemic cetirizine, or a pharmaceutically acceptable salt thereof, aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof,and optionally a decongestant, as the active ingredient. Thecompositions may also contain a pharmaceutically acceptable carrier orexcipient, and, optionally, other therapeutic ingredients.

[0049] The compositions for use in the methods of the present inventioncan include suitable excipients or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like.

[0050] Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, gel caps, syrups, elixirs, gels, powders,magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs,suppositories, nasal or oral sprays, aerosols, and the like.

[0051] Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit form, in which casesolid pharmaceutical carriers are employed. If desired, tablets may becoated by standard aqueous or nonaqueous techniques.

[0052] In addition to the common dosage forms set out above, thecompound for use in the methods of the present invention may also beadministered by controlled release means and/or delivery devices such asthose described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, the disclosures of which are expresslyincorporated herein by reference thereto.

[0053] Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

[0054] For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent.

[0055] The invention is further defined by reference to the followingexamples describing in detail the preparation of the composition and thecompositions used in the methods of the present invention, as well astheir utility. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced which arewithin the scope of this invention.

5. EXAMPLES 5.1 Synthesis of Racemic Cetirizine

[0056] The dihydrochloride salt of(±)2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid may be prepared according to the method of Cossement et al.,disclosed in British Patent Application No. 2,225,321.

[0057] In 250 ml of ethanol, 23 g (0.062 mole) of racemic2-[2-[-4-[(4-chlorophenylmethyl]-1-piperazinyl]ethoxy]-acetonitrile and31 ml of a 4N ethanolic solution of potassium hydroxide are introducedsuccessively into a three-necked round-bottomed flask equipped with amechanical stirrer, a condenser and a thermometer. The reaction mixtureis refluxed for 10 hours, while stirring. It is then allowed to cool andits pH is brought to 6 by addition of 37% concentrated hydrochloricacid. The ethanol is evaporated and the reaction mixture is diluted with100 ml of water and extracted three times with 200 ml ofdichloromethane.

[0058] The organic phases are combined, dried over magnesium sulphate,filtered, and concentrated in a rotary evaporator. An oil is obtainedand is allowed to crystallize by addition of 100 ml of 2-butanone, whilehot. The solid formed is filtered, washed, and dried to obtain 18.9 g ofracemic2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid.

[0059] The acid is resuspended in 150 ml of water, the pH of which isbrought to 0.8 by addition of concentrated hydrochloric acid. Theaqueous solution is concentrated on a rotary evaporator and the residueis then diluted by addition of 75 ml of 2-butanone. This inducescrystallization of racemic2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid dihydrochloride. The crystals are filtered off and dried to yield21.7 g (75.9%) of product. The melting point of the crystals is 220.15°C. as measured by differential scanning calorimetry (DSC).

5.2 Alternative Synthesis of Racemic Cetirizine

[0060] Alternatively,(±)2-[2-[-4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid may be prepared according to the method of Baltes et al. disclosedin U.S. Pat. No. 4,525,358. In this method,2-[2-[4-Diphenylmethyl)-1-piperazinyl]ethoxy]-acetamide dihydrochlorideis first synthesized as follows.

[0061] A mixture of 37.8 g (0.15 mole) of 1-(diphenylmethyl)-piperazine,27.5 g (0.2 mole of 2-(2-chloroethoxy)-acetamide and 26.5 g of anhydroussodium carbonate in 120 ml of xylene is heated for 4 hours to 90° C. to120° C. Thereafter, 120 ml of benzene are added to the reaction mixture,the precipitate formed is filtered off and the organic phase isextracted with dilute hydrochloric acid (30 ml of concentratedhydrochloric acid and 100 ml of water). 40 ml of a concentrated aqueoussolution of sodium hydroxide are added, followed by extraction withbenzene. The benzene solution is washed with water, dried over anhydroussodium carbonate and the benzene is evaporated off to dryness. Theevaporation residue is titrated with diethyl ether and left tocrystallize. 2-[2-[4-Diphenylmethyl)-1-piperazinyl]ethoxy]-acetamide isobtained in a yield of 73% (M.P. 119° C.-120° C.).

[0062] In the second part of the synthesis, a mixture of 19 g (0.054mole) of 2-[2-[4-diphenylmethyl)-1-piperazinyl]ethoxy[-acetamide in 200ml of ethanol and 27 ml of a 4 N ethanolic solution of sodium hydroxideis heated under reflux for 3 hours. The reaction mixture is adjustedwith 29.7 ml of 3.61 N hydrochloric acid to a pH of 6.3, whereafter theethanol is evaporated off in a vacuum. The precipitate obtained isfiltered off. After evaporation of the solvent, 17.4 g of crude2-[2-[4-diphenylmethyl)-1-piperazinyl]ethoxy]-acetic acid are obtained(yield 91%; M.P. 100° C.). This product may be purified by conventionalmeans known to those skilled in the art.

5.3 Synthesis of Optically Pure (+) Cetirizine

[0063] The dihydrochloride salt of(+)2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid may be prepared according to the method of Cossement et al.disclosed in British Patent Application No. 2,225,321.

[0064] 9.42 g (0.0255 mole) of levorotatory2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyllethoxy]-acetonitrile are introduced into a reactor equipped with amechanical stirrer, a condenser, a thermometer, and a dropping funneland are heated to 45° C., while stirring. 15 ml of 37% concentratedhydrochloric acid are then added. The temperature of the reactionmixture rises to 92° C. The temperature of the reaction mixture ismaintained at 60° C. for 60 minutes while stirring. The reaction mixtureis allowed to cool and is concentrated on a rotary evaporator. Theresidue is then taken up in 50 ml of water. The pH of the reactionmixture is brought to 5 by addition of sodium hydroxide and the mixtureis extracted with several successive fractions of dichloromethane. Theorganic phases are combined and dried over magnesium sulphate and thesolvent is removed on a rotary evaporator. 9.6 g of the free acid of thefinal product are thus obtained in the form of a beige powder, which arethen converted into the dihydrochloride by means of a solution ofhydrochloric acid in acetone. The dihydrochloride is crystallized fromthis solution. After filtration and drying, 9.8 g of(+)2-[2-(4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]-aceticacid dihydrochloride are obtained. The purity of this product, obtainedin 83% yield, may be measured by high performance liquid chromatographywith a chiral stationary phase of a α₁-AGP (from the LKB Company). It istypically 95% with respect to the dextrorotatory enantiomer. The producthas a melting point of 199-201° C. (224.4° C. as measured by DSC), andan [α] of +9.4° (c=1, water).

5.4 Synthesis of Optically Pure (−) Cetirizine

[0065] This product is obtained by the method described in example 5.3,but starting from dextrorotatory1-[(4-chlorophenyl)phenylmethyl)-piperazine, the latter being obtainedby treating the racemate with (2S,3S)-tartaric acid using techniquesknown to those skilled in the art.

[0066] The dihydrochloride salt of(−)2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-aceticacid is obtained in yields and with a purity very close to thoseobtained for the dextrorotatory acid dihydrochloride: 95% measured byhigh performance liquid chromatography with a chiral stationary phase ofα₁-AGP (from the LKB Company). The product has a melting point of198-200° C. (220.7° C. as measured by DSC), but decomposes upon melting.

[0067] While the present invention has been described with respect tothe particular embodiments, it will be apparent to those skilled in theart that various changes and modifications may be made without departingfrom the spirit and scope of the invention as defined in the claims.Such modifications are also intended to fall within the scope of theappended claims.

What is claimed is:
 1. A method of treating or preventing asthma or asymptom thereof in a human which comprises administering to a human: (a)a therapeutically effective amount of cetirizine or a pharmaceuticallyacceptable salt thereof, and; (b) a therapeutically effective amount ofa leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.2. A method of treating or preventing asthma or a symptom thereof in ahuman which comprises administering to a human a composition, saidcomposition comprising: (a) a therapeutically effective amount ofcetirizine or a pharmaceutically acceptable salt thereof; (b) atherapeutically effective amount of leukotriene inhibitor, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activatingprotein antagonists, and leukotriene receptor antagonists, and mixturesthereof, and; (c) a pharmaceutically acceptable carrier or excipient. 3.The method of claim 1 or 2 wherein the administering further comprises atherapeutically effective amount of a decongestant, or apharmaceutically acceptable salt thereof.
 4. The method of claim 1 or 2wherein said human has asthma.
 5. The method of claim 1 or 2 whereinsaid effective amount of cetirizine is an effective amount of racemiccetirizine.
 6. The method of claim 1 or 2 wherein said cetirizine is theoptically pure (+) enantiomer.
 7. The method of claim 1 or 2 whereinsaid cetirizine is the optically pure (−) enantiomer.
 8. A method oftreating or preventing dermatitis in a human which comprisesadministering to a human a therapeutically effective amount ofcetirizine or a pharmaceutically acceptable salt thereof, and atherapeutically effective amount of a leukotriene inhibitor, or apharmaceutically acceptable salt thereof.
 9. A method of treating orpreventing dermatitis in a human which comprises administering to ahuman a therapeutically effective amount of a composition, saidcomposition comprising: (a) cetirizine or a pharmaceutically acceptablesalt thereof; (b) a therapeutically effective amount of leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof, selected fromthe group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenaseactivating protein antagonists, and leukotriene receptor antagonists,and mixtures thereof, and; (c) a pharmaceutically acceptable carrier orexcipient.
 10. The method of claim 8 or 9 wherein the administeringfurther comprises a therapeutically effective amount of a decongestant,or a pharmaceutically acceptable salt thereof.
 11. The method of claim 8or 9 wherein said effective amount of cetirizine is an effective amountof racemic cetirizine.
 12. The method of claim 8 or 9 wherein saidcetirizine is the optically pure (+) enantiomer.
 13. The method of claim8 or 9 wherein said cetirizine is the optically pure (−) enantiomer. 14.A method of treating or preventing allergic rhinitis in a human whichcomprises administering to a human a therapeutically effective amount ofcetirizine or a pharmaceutically acceptable salt thereof, and atherapeutically effective amount of a leukotriene inhibitor, or apharmaceutically acceptable salt thereof.
 15. A method of treating orpreventing allergic rhinitis in a human which comprises administering toa human a therapeutically effective amount of a composition, saidcomposition comprising: (a) cetirizine or a pharmaceutically acceptablesalt thereof; (b) a therapeutically effective amount of leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof, selected fromthe group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenaseactivating protein antagonists, and leukotriene receptor antagonists,and mixtures thereof, and; (c) a pharmaceutically acceptable carrier orexcipient.
 16. The method of claim 14 or 15 wherein the administeringfurther comprises a therapeutically effective amount of a decongestant,or a pharmaceutically acceptable salt thereof.
 17. The method of claim14 or 15 wherein said effective amount of cetirizine is an effectiveamount of racemic cetirizine.
 18. The method of claim 14 or 15 whereinsaid cetirizine is the optically pure (+) enantiomer.
 19. The method ofclaim 14 or 15 wherein said cetirizine is the optically pure (−)enantiomer.
 20. A method of treating or preventing inflammation in ahuman which comprises administering to a human a therapeuticallyeffective amount of cetirizine or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof.
 21. A methodof treating or preventing inflammation in a human which comprisesadministering to a human a therapeutically effective amount of acomposition, said composition comprising: (a) cetirizine or apharmaceutically acceptable salt thereof; (b) a therapeuticallyeffective amount of leukotriene inhibitor, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of5-lipoxygenase inhibitors, 5-lipoxygenase activating proteinantagonists, and leukotriene receptor antagonists, and mixtures thereof,and; (c) a pharmaceutically acceptable carrier or excipient.
 22. Themethod of claim 20 or 21 wherein the administering further comprises atherapeutically effective amount of a decongestant, or apharmaceutically acceptable salt thereof.
 23. The method of claim 20 or21 wherein said effective amount of cetirizine is an effective amount ofracemic cetirizine.
 24. The method of claim 20 or 21 wherein saidcetirizine is the optically pure (+) enantiomer.
 25. The method of claim20 or 21 wherein said cetirizine is the optically pure (−) enantiomer.26. A method of treating or preventing a condition responsive toleukotriene inhibition which comprises administering to a human atherapeutically effective amount of cetirizine or a pharmaceuticallyacceptable salt thereof, and a therapeutically effective amount of aleukotriene inhibitor, or a pharmaceutically acceptable salt thereof.27. A method of treating or preventing a condition responsive toleukotriene inhibition which comprises administering to a human atherapeutically effective amount of a composition, said compositioncomprising: (a) cetirizine or a pharmaceutically acceptable saltthereof; (b) a therapeutically effective amount of leukotrieneinhibitor, or a pharmaceutically acceptable salt thereof, selected fromthe group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenaseactivating protein antagonists, and leukotriene receptor antagonists,and mixtures thereof; and (c) a pharmaceutically acceptable carrier orexcipient.
 28. The method of claim 26 or 27 wherein the administeringfurther comprises a therapeutically effective amount of a decongestant,or a pharmaceutically acceptable salt thereof.
 29. The method of claim26 or 27 wherein said cetirizine is racemic cetirizine.
 30. The methodof claim 26 or 27 wherein said cetirizine is the optically pure (+)enantiomer.
 31. The method of claim 26 or 27 wherein said cetirizine isthe optically pure (−) enantiomer.
 32. The method of claim 26 or 27wherein the condition responsive to leukotriene inhibition comprisesasthma or a symptom thereof.
 33. The method of claim 26 or 27 whereinthe condition responsive to leukotriene inhibition comprises an allergiccondition.
 34. The method of claim 26 or 27 wherein the conditionresponsive to leukotriene inhibition comprises inflammation.
 35. Themethod of claim 1, 8, 14, 20, or 26 wherein the amount of cetirizine isfrom about 0.1 mg to about 50 mg per day.
 36. The method of claim 35wherein the cetirizine is racemic cetirizine present in an amount fromabout 5 mg to about 25 mg per day.
 37. The method of claim 35 whereinthe cetirizine is (+) cetirizine.
 38. The method of claim 35 wherein thecetirizine is (−) cetirizine.
 39. The method of claim 1, 8, 14, 20, or26 wherein the leukotriene inhibitor is a 5-lipoxygenase inhibitor. 40.The method of claim 39 wherein said 5-lipoxygenase inhibitor is selectedfrom the group consisting of zileuton, docebenone, piripost, ICI-D2318,and mixtures thereof.
 41. The method of claim 1, 8, 14, 20 or 26 whereinsaid leukotriene inhibitor is a 5-lipoxygenase activating proteinantagonist.
 42. The method of claim 41 wherein said 5-lipoxygenaseactivating protein antagonist is selected from the group consisting ofMK-591, MK-886, and mixtures thereof.
 43. The method of claim 1, 8, 14,20 or 26 wherein said leukotriene inhibitor is a leukotriene receptorantagonist.
 44. The method of claim 43 wherein said leukotriene receptorantagonist is selected from the group consisting of zafirlukast,montelukast, pranlukast, sodium1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)-ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)-cyclopropaneacetate,1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)-phenyl)propyl)thio)methyl)cyclopropaneaceticacid or salts thereof, and mixtures thereof.
 45. A pharmaceuticalcomposition which comprises: (a) a therapeutically effective amount ofcetirizine or a pharmaceutically acceptable salt thereof; (b) atherapeutically effective amount of a leukotriene inhibitor, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activatingprotein antagonists, and leukotriene receptor antagonists, and mixturesthereof; and (c) a pharmaceutically acceptable carrier or excipient. 46.A pharmaceutical composition which comprises from about 0.1 mg to about50 mg of cetirizine or a pharmaceutically acceptable salt thereof, andfrom about 2 mg to about 100 mg of leukotriene receptor antagonist, or apharmaceutically acceptable salt thereof.
 47. A pharmaceuticalcomposition which comprises from about 0.1 mg to about 50 mg ofcetirizine or a pharmaceutically acceptable salt thereof, and from about20 mg to about 2500 mg of 5-lipoxygenase inhibitor, or apharmaceutically acceptable salt thereof.
 48. A pharmaceuticalcomposition which comprises from about 0.1 mg to about 50 mg ofcetirizine or a pharmaceutically acceptable salt thereof, and from about20 mg to about 2500 mg of 5-lipoxygenase activating protein antagonist,or a pharmaceutically acceptable salt thereof.
 49. The pharmaceuticalcomposition of claim 45 which further comprises a therapeuticallyeffective amount of a decongestant, or a pharmaceutically acceptablesalt thereof.
 50. The composition of claim 45, 46, 47, or 48 whereinsaid effective amount of cetirizine is an effective amount of racemiccetirizine.
 51. The composition of claim 45, 46, 47, or 48 wherein saideffective amount of cetirizine is an effective amount of (+)cetirizine.52. The composition of claim 45, 46, 47, or 48 wherein said effectiveamount of cetirizine is an effective amount of (−) cetirizine.